This program project is in response to RFAAI-93-10 "Mechanisms of Oral Tolerization and Immunization." The purpose of the program project is to understand basic mechanisms of oral tolerance to autoantigens both in animal models and human disease states. The investigators have performed a series of experiments demonstrating that oral tolerance is effective in treating autoimmune diseases in animals which led them to conduct a series of human trials in multiple sclerosis and rheumatoid arthritis that demonstrated positive immunologic and clinical effects of oral tolerization. Though oral tolerization is a long-recognized method of inducing peripheral immune tolerance, the basic mechanisms underlying oral tolerance as applied to the treatment of human autoimmune disease remain to be defined. The theme of the program project is to define which mechanisms of peripheral immune tolerance as related to active suppression, clonal anergy, clonal deletion occur following oral tolerance both in animals and in man. Project 1 will focus on the role of cytokines IL-4, IL-10, and TGF/beta in the mediation of oral tolerance of that affect the initiation of oral tolerance using cytokine transgenic and knockout animals. The requirement for co-stimulatory molecules in initiating oral tolerance will be studied. The factors which lead to anergy vs. active suppressive will be investigated in MBP-TcR transgenic animals. Project 2 will characterize the T cells mediating oral tolerance, and investigate differential epitope recognition. This will be done by generating T cell clones and hybridomas from orally tolerized animals. In addition, immune effects following neonatal administration of antigen via the oral route will be studied. Project 3 will study oral tolerance to autoantigens in humans, determining the degree to which active suppression, clonal anergy and clonal deletion occur in multiple sclerosis patients orally tolerized to myelin antigens and in rheumatoid arthritis patients orally tolerized to type II collagen. In summary, the program project presents and integrated approach for the study of basic mechanisms of antigen-driven peripheral immune tolerance induced by orally administered autoantigens in animals and humans. The program project encompasses both basic science and clinical immunologic investigations that will increase our understanding of the mechanisms of oral tolerance so that they may be ultimately applied to human disease states.